tbuckley/cabot-search huggingface dataset:
KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency–Related Polycystic Kidney Disease
Authors: Gyuyeong Rah, Hwayeon Cha, Joohee Kim, Jieun Song, Hyunho Kim, Yun Kyu Oh, Curie Ahn, Minyong Kang, Jongmin Kim, Kyung Hyun Yoo, Min Jung Kim, Hyuk Wan Ko, Je Yeong Ko, Jong Hoon Park
Journal: Journal of the American Society of Nephrology (2022)

Ciliogenesis-associated kinase 1 (CILK1) is a ciliary gene that localizes in primary cilia and regulates ciliary transport. Mutations in CILK1 cause various ciliopathies. However, the pathogenesis of CILK1-deficient kidney disease is unknown.To examine whether CILK1 deficiency causes PKD accompanied by abnormal cilia, we generated mice with deletion of Cilk1 in cells of the renal collecting duct. A yeast two-hybrid system and coimmunoprecipitation (co-IP) were used to identify a novel regulator, kinesin light chain-3 (KLC3), of ciliary trafficking and cyst progression in the Cilk1-deficient model. Immunocytochemistry and co-IP were used to examine the effect of KLC3 on ciliary trafficking of the IFT-B complex and EGFR. We evaluated the effects of these genes on ciliary trafficking and cyst progression by modulating CILK1 and KLC3 expression levels.CILK1 deficiency leads to PKD accompanied by abnormal ciliary trafficking. KLC3 interacts with CILK1 at cilia bases and is increased in cyst-lining cells of CILK1-deficient mice. KLC3 overexpression promotes ciliary recruitment of IFT-B and EGFR in the CILK1 deficiency condition, which contributes to the ciliary defect in cystogenesis. Reduction in KLC3 rescued the ciliary defects and inhibited cyst progression caused by CILK1 deficiency.Our findings suggest that CILK1 deficiency in renal collecting ducts leads to PKD and promotes ciliary trafficking via increased KLC3.
Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment
Authors: Matthew B. Yurgelun, Hajime Uno, C. Sloane Furniss, Chinedu Ukaegbu, Miki Horiguchi, Amal Yussuf, Holly LaDuca, Anu Chittenden, Judy E. Garber, Sapna Syngal
Journal: Journal of Clinical Oncology (2022)

PURPOSE With the availability of multigene panel testing (MGPT) for hereditary cancer risk assessment, clinicians need to assess the likelihood of pathogenic germline variants (PGVs) across numerous genes in parallel. This study's aim was to develop and validate a clinical prediction model (PREMMplus) for MGPT risk assessment. MATERIALS AND METHODS PREMMplus was developed in a single-institution cohort of 7,280 individuals who had undergone MGPT. Logistic regression models with Least Absolute Shrinkage and Selection Operator regularization were used to examine candidate predictors (age, sex, ethnicity, and personal/family history of 18 cancers/neoplasms) to estimate one's likelihood of carrying PGVs in 19 genes (broadly categorized by phenotypic overlap and/or relative penetrance: 11 category A [ APC , BRCA1 / 2 , CDH1 , EPCAM , MLH1 , MSH2 , MSH6 , biallelic MUTYH , PMS2 , and TP53 ] and eight category B genes [ ATM , BRIP1 , CDKN2A , CHEK2 , PALB2 , PTEN , RAD51C , and RAD51D ]). Model performance was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MGPT ascertained from clinic- and laboratory-based settings, respectively. RESULTS PREMMplus (score ≥ 2.5%) had 93.9%, 91.7%, and 89.3% sensitivity and 98.3%, 97.5%, and 97.8% negative-predictive value (NPV) for identifying category A gene PGV carriers in the development and validation cohorts, respectively. PREMMplus assessment (score ≥ 2.5%) had 89.9%, 85.6%, and 84.2% sensitivity and 95.0%, 93.5%, and 93.5% NPV, respectively, for identifying category A/B gene PGV carriers. Decision curve analyses support MGPT for individuals predicted to have ≥ 2.5% probability of a PGV. CONCLUSION PREMMplus accurately identifies individuals with PGVs in a diverse spectrum of cancer susceptibility genes with high sensitivity/NPV. Individuals with PREMMplus scores ≥ 2.5% should be considered for MGPT.
Kidney Failure Alters Parathyroid Pin1 Phosphorylation and Parathyroid Hormone mRNA-Binding Proteins, Leading to Secondary Hyperparathyroidism
Authors: Alia Hassan, Yael E. Pollak, Rachel Kilav-Levin, Justin Silver, Nir London, Morris Nechama, Iddo Z. Ben-Dov, Tally Naveh-Many
Journal: Journal of the American Society of Nephrology (2022)

Secondary hyperparathyroidism (SHP) is a common complication of CKD that increases morbidity and mortality. In experimental SHP, increased parathyroid hormone (PTH) expression is due to enhanced PTH mRNA stability, mediated by changes in its interaction with stabilizing AUF1 and destabilizing KSRP. The isomerase Pin1 leads to KSRP dephosphorylation, but in SHP parathyroid Pin1 activity is decreased and hence phosphorylated KSRP fails to bind PTH mRNA, resulting in high PTH mRNA stability and levels. The up- and downstream mechanisms by which CKD stimulates the parathyroid glands remain elusive.Adenine-rich high-phosphate diets induced CKD in rats and mice. Parathyroid organ cultures and transfected cells were incubated with Pin1 inhibitors for their effect on PTH expression. Mass spectrometry was performed on both parathyroid and PTH mRNA pulled-down proteins.CKD led to changes in rat parathyroid proteome and phosphoproteome profiles, including KSRP phosphorylation at Pin1 target sites. Furthermore, both acute and chronic kidney failure led to parathyroid-specific Pin1 Ser16 and Ser71 phosphorylation, which disrupts Pin1 activity. Pharmacologic Pin1 inhibition, which mimics the decreased Pin1 activity in SHP, increased PTH expression ex vivo in parathyroid glands in culture and in transfected cells through the PTH mRNA-protein interaction element and KSRP phosphorylation.Kidney failure leads to loss of parathyroid Pin1 activity by inducing Pin1 phosphorylation. This predisposes parathyroids to increase PTH production through impaired PTH mRNA decay that is dependent on KSRP phosphorylation at Pin1-target motifs. Pin1 and KSRP phosphorylation and the Pin1-KSRP-PTH mRNA axis thus drive SHP.
Congenital Malformations
Authors: Josef Warkany, Harold Kalter
Journal: New England Journal of Medicine (1961)

Other viral diseases. The discovery that rubella could produce congenital malformations aroused great interest in the possibility that other infectious diseases during pregnancy would have similar effects. Many such diseases have been studied from this point of view, and although for some the evidence was negative, for others it was conflicting. Early studies, usually retrospective, were reviewed by Wesselhoeft,164 who believed, despite the apparently positive findings of some investigators,128, 165 , 166 concerning mumps, measles and chicken pox, that no significant evidence had been obtained of any association between the disease and congenital malformations.Later studies, usually prospective and of larger proportions than . . .
Extended HPV Genotyping for Risk Assessment of Cervical Intraepithelial Neoplasia Grade 2/3 or Worse in a Cohort Study
Authors: Xiao Li, Xuan Rao, Ming-Jing Wei, Wei-Guo Lu, Xing Xie, Xin-Yu Wang
Journal: Journal of the National Comprehensive Cancer Network (2022)

Background: We sought to identify the absolute risk of specific HPV genotype for cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/3+) and to develop a risk-based management strategy in an HPV-positive population. Methods: HPV genotyping was performed based on a 3-year cervical cancer screening cohort. The study endpoints were histologic CIN2+/3+. The prevalence of specific HPV genotype was calculated by minimum, any type, and hierarchical attribution estimate. The absolute CIN2+/3+ risks of specific HPV genotype were estimated and risk-based management strategy was established according to the American Society for Colposcopy and Cervical Pathology guideline. The efficacy of conventional and risk-based management strategies for non-16/18 HPVs were further evaluated. Results: Eligible data were available for 8,370 women with a median age of 48 years (interquartile range, 42–53 years). At baseline, there were 1,062 women with HPV-positive disease, including 424 with multiple and 639 with single infections. CIN2+/3+ cases represented 113/74, 23/8, 20/7, and 52/31 patients at baseline and first-, second-, and third-year visits, respectively. Women with multiple HPV infections at baseline were more prone to persistent infection than those with single infection ( P &lt;.0001). HPV16 and HPV52 were the top 2 ranking among baseline and 3-year cumulative CIN2+/3+ cases. Based on the absolute risk of specific HPV genotype combined with cytology for CIN2+/3+, all non-16/18 HPVs were divided into 4 risk-stratified groups. Compared with conventional strategy, the risk-based strategy had higher specificity ( P =.0000) and positive predictive value ( P =.0322) to detect CIN3+ and needed fewer colposcopies for each CIN3+ case. Conclusions: Based on our study findings, we propose a new extended HPV genotyping protocol, which would provide a better strategy for achieving precise risk-based management of HPV-positive populations.
NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022
Authors: Thomas W. Flaig, Philippe E. Spiess, Michael Abern, Neeraj Agarwal, Rick Bangs, Stephen A. Boorjian, Mark K. Buyyounouski, Kevin Chan, Sam Chang, Terence Friedlander, Richard E. Greenberg, Khurshid A. Guru, Harry W. Herr, Jean Hoffman-Censits, Amar Kishan, Shilajit Kundu, Subodh M. Lele, Ronac Mamtani, Vitaly Margulis, Omar Y. Mian, Jeff Michalski, Jeffrey S. Montgomery, Lakshminarayanan Nandagopal, Lance C. Pagliaro, Mamta Parikh, Anthony Patterson, Elizabeth R. Plimack, Kamal S. Pohar, Mark A. Preston, Kyle Richards, Wade J. Sexton, Arlene O. Siefker-Radtke, Matthew Tollefson, Jonathan Tward, Jonathan L. Wright, Mary A. Dwyer, Carly J. Cassara, Lisa A. Gurski
Journal: Journal of the National Comprehensive Cancer Network (2022)

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.
Association of Polypharmacy and Potentially Inappropriate Medications With Frailty Among Older Adults With Blood Cancers
Authors: Tammy T. Hshieh, Clark DuMontier, Timothy Jaung, Nupur E. Bahl, Chelsea E. Hawley, Lee Mozessohn, Richard M. Stone, Robert J. Soiffer, Jane A. Driver, Gregory A. Abel
Journal: Journal of the National Comprehensive Cancer Network (2022)

Polypharmacy and potentially inappropriate medications (PIMs) are common among older adults with blood cancers, but their association with frailty and how to manage them optimally remain unclear.
Perioperative Systemic Therapy for Resectable Non–Small Cell Lung Cancer
Authors: Bharathi Muthusamy, Pradnya D. Patil, Nathan A. Pennell
Journal: Journal of the National Comprehensive Cancer Network (2022)

Despite remarkable treatment advancements in patients with advanced non–small cell lung cancer (NSCLC), recurrence rates for those with resectable, early-stage disease remains high. Immune checkpoint inhibitors and targeted therapies are 2 promising treatment modalities that may improve survival outcomes for patients with resected NSCLC when moved from the advanced stage to the curable setting. There are many clinical studies that have evaluated or are currently evaluating immunotherapy or targeted therapy in the perioperative setting, and recent trials such as CheckMate 816, ADAURA, and IMpower010 have led to new approvals and demonstrated the promise of this approach. This review discusses recent and ongoing neoadjuvant and adjuvant systemic therapy trials in NSCLC, and where the field may be going in the near future.
Application of the Socioecological Model to Regional Clinical Trials: A Paradigm-Shift to Advance Scientific Discovery and Prognostic Modeling
Authors: Shawna L. Ehlers
Journal: Journal of the National Comprehensive Cancer Network (2022)

"Application of the Socioecological Model to Regional Clinical Trials: A Paradigm-Shift to Advance Scientific Discovery and Prognostic Modeling" published on Aug 2022 by National Comprehensive Cancer Network.
Immunotherapy-Based Neoadjuvant Treatment of Advanced Microsatellite Instability–High Gastric Cancer: A Case Series
Authors: Louisa Liu, Yanghee Woo, Massimo D’Apuzzo, Laleh Melstrom, Mustafa Raoof, Yu Liang, Michelle Afkhami, Stanley R. Hamilton, Joseph Chao
Journal: Journal of the National Comprehensive Cancer Network (2022)

Despite the use of first-line therapies like fluoropyrimidine and platinum-based cytotoxic chemotherapy, gastric cancer (GC) continues to carry a poor prognosis. Recent subgroup analyses of first-line phase III trials have demonstrated that patients with microsatellite instability-high (MSI-H) metastatic GC derive significant improvement in survival rates when immune checkpoint inhibitors (ICIs) are combined with chemotherapy compared with chemotherapy alone. However, it remains to be seen whether the success of ICIs in the metastatic setting can be translated into earlier stages of GC with resectable disease. We report 6 cases of locally advanced, nonmetastatic MSI-H GC that all demonstrated favorable response following treatment with pembrolizumab in addition to neoadjuvant chemotherapy. With the exception of immune-related colitis in one patient, pembrolizumab was well-tolerated. To our knowledge, this is the first reported US case series of patients treated with an ICI in combination with neoadjuvant chemotherapy for advanced, nonmetastatic, resectable or unresectable MSI-H GC.
Impact of Genetic Counseling on Patient-Reported Electronic Cancer Family History Collection
Authors: Rebecca A. Vanderwall, Alison Schwartz, Lindsay Kipnis, Catherine M. Skefos, Samantha M. Stokes, Nizar Bhulani, Michelle Weitz, Rebecca Gelman, Judy E. Garber, Huma Q. Rana
Journal: Journal of the National Comprehensive Cancer Network (2022)

Cancer family history is a vital part of cancer genetic counseling (GC) and genetic testing (GT), but increasing indications for germline cancer GT necessitate less labor-intensive models of collection. We evaluated the impact of GC on patient pedigrees generated by an electronic cancer family history questionnaire (eCFHQ).An Institutional Review Board-approved review of pedigrees collected through an eCFHQ was conducted. Paired pre-GC and post-GC pedigrees (n=1,113 each group) were analyzed independently by cancer genetic counselors for changes in patient-reported clinical history and to determine whether the pedigrees met NCCN GT criteria. Discrepancy in meeting NCCN GT criteria between pre-GC and post-GC pedigrees was the outcome variable of logistic regressions, with patient and family history characteristics as covariates.Overall, 780 (70%) patients had cancer (affected), 869 (78%) were female, and the median age was 57 years (interquartile range, 45-66 years; range, 21-91 years). Of the 1,113 pairs of pre-GC and post-GC pedigrees analyzed, 85 (8%) were blank, 933 (84%) were not discrepant, and 95 (9%) were discrepant in meeting any NCCN GT criteria. Of the discrepant pedigrees, n=79 (83%) became eligible for testing by at least one of the NCCN GT criteria after GC. Patients with discrepant pedigrees were more likely to report no or unknown history of GT (odds ratio [OR], 4.54; 95% CI, 1.66-18.70; P=.01, and OR, 18.47; 95% CI, 5.04-88.73; P<.0001, respectively) and belonged to racially and/or ethnically underrepresented groups (OR, 1.91; 95% CI, 1.08-3.25; P=.02).For most patients (84%), a standalone eCFHQ was sufficient to determine whether NCCN GT criteria were met. More research is needed on the performance of the eCFHQ in diverse patient populations.
Radiographic and Serologic Response to First-Line Chemotherapy in Unresected Localized Pancreatic Cancer
Authors: Caitlin A. Hester, Giampaolo Perri, Laura R. Prakash, Jessica E. Maxwell, Naruhiko Ikoma, Michael P. Kim, Ching-Wei D. Tzeng, Brandon Smaglo, Robert Wolff, Milind Javle, Michael J. Overman, Jeffrey E. Lee, Matthew H.G. Katz
Journal: Journal of the National Comprehensive Cancer Network (2022)

Background: This study aimed to determine the clinical relevance of putative radiographic and serologic metrics of chemotherapy response in patients with localized pancreatic cancer (LPC) who do not undergo pancreatectomy. Studies evaluating the response of LPC to systemic chemotherapy have focused on histopathologic analyses of resected specimens, but such specimens are not available for patients who do not undergo resection. We previously showed that changes in tumor volume and CA 19-9 levels provide a clinical readout of histopathologic response to preoperative therapy. Methods: Our institutional database was searched for patients with LPC who were treated with first-line chemotherapy between January 2010 and December 2017 and did not undergo pancreatectomy. Radiographic response was measured using RECIST 1.1 and tumor volume. The volume of the primary tumor was compared between pretreatment and posttreatment images. The percentage change in tumor volume (%Δvol) was calculated as a percentage of the pretreatment volume. Serologic response was measured by comparing pretreatment and posttreatment CA 19-9 levels. We established 3 response groups by combining these metrics: (1) best responders with a decline in %Δvol in the top quartile and in CA 19-9, (2) nonresponders with an increase in %Δvol and in CA 19-9, and (3) other patients. Results: This study included 329 patients. Individually, %Δvol and change in CA 19-9 were associated with overall survival (OS) ( P ≤.1), but RECIST 1.1 was not. In all, 73 patients (22%) were best responders, 42 (13%) were nonresponders, and there were 214 (65%) others. Best responders lived significantly longer than nonresponders and others (median OS, 24 vs 12 vs 17 months, respectively; P &lt;.01). A multivariable model adjusting for type of chemotherapy regimen, number of chemotherapy doses, and receipt of radiotherapy showed that best responders had longer OS than did the other cohorts (hazard ratio [HR], 0.35; 95% CI, 0.21–0.58 for best responders, and HR, 0.55; 95% CI, 0.37–0.83 for others). Conclusions: Changes in tumor volume and serum levels of CA 19-9—but not RECIST 1.1—represent reliable metrics of response to systemic chemotherapy. They can be used to counsel patients and families on survival expectations even if pancreatectomy is not performed.
Regional Variations in Clinical Trial Outcomes in Oncology
Authors: Brooke E. Wilson, Sallie-Anne Pearson, Michael B. Barton, Eitan Amir
Journal: Journal of the National Comprehensive Cancer Network (2022)

It is unknown how often regional differences in oncology trials are observed. Based on our study findings, we quantified regional variation in registration studies in oncology and developed a question guide to help clinicians evaluate regional differences.Using FDA archives, we identified registration studies in solid tumor malignancies from 2010 to 2020. We extracted the baseline study characteristics and participating countries and determined whether the primary publication reported a regional subgroup analysis. For studies presenting outcomes stratified by region, we extracted the stratified hazard ratios (HRs) and extracted or calculated the test for heterogeneity. We performed a random effects meta-analysis and a pairwise comparison to determine whether outcomes differed between high-income versus mixed-income regions.We included 147 studies in our final analysis. Studies supporting FDA drug approval have become increasingly multinational over time (β = 0.5; P=.04). The median proportion of countries from high-income groups was 81.2% (range, 44%-100%), with no participation from low-income countries in our cohort. Regional subgroup analysis was presented for 78 studies (53%). Regional heterogeneity was found in 17.8% (8/45) and 18% (8/44) of studies presenting an overall survival (OS) and progression-free survival endpoint, respectively. After grouping regions by income level, we found no difference in OS outcomes in high-income regions compared with mixed-income regions (n=20; HR, 0.95; 95% CI, 0.84-1.07). To determine whether regional variation is genuine, clinicians should evaluate the data according to the following 5 questions: (1) Are the regional groupings logical? (2) Is the regional difference on an absolute or relative scale? (3) Is the regional difference consistent and plausible? (4) Is the regional difference statistically significant? (5) Is there a clinical explanation?As registration studies in oncology become increasingly international, regional variations in trial outcomes may be detected. The question guide herein will help clinicians determine whether regional variations are likely to be clinically meaningful or statistical anomalies.